Piperidine derivatives having tachykinin antagonist activity

ABSTRACT

The present invention relates to piperidine derivatives of formula (I): ##STR1## wherein the substituents R 1 , R 3 , R 4  and R 5  are as defined in the specification and claims, and the substituent R 2  is ##STR2## The pharmaceutically acceptable salts and solvates of these piperidine derivatives are also described. The invention also relates to processes for the preparation of the piperidine derivatives, and to their use in the treatment of conditions mediated by tachykinins.

The present invention relates to piperidine derivatives, to processesfor their preparation, pharmaceutical compositions containing them andtheir medical use.

3-Aminopiperidine derivatives described as having substance P antagonistactivity are disclosed in, for example, PCT Patent ApplicationsWO93/00331, WO93/01170 and WO94/13663.

In particular the invention relates to novel compounds which are potentand specific antagonists of tachykinins, including substance P and otherneurokinins.

The present invention provides compounds of formula (I) ##STR3## whereinR¹ is --O--(CH₂)_(p) C₃₋₇ cycloalkyl, --O--C₁₋₇ fluoroalkyl, or--O--(CH₂)_(n) X;

R² is ##STR4## R³ is a hydrogen or halogen atom; R⁴ and R⁵ may eachindependently represent a hydrogen or halogen atom, or a

C₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl group;

X is selected from C(O)--NR⁷ R⁸, C(O)R⁹, NR⁷ R⁸, SO₂ NR⁷ R⁸, NHSO₂ R⁹,S(O)_(s) R⁹, OC₁₋₄ alkyl, NO₂, CO₂ H, CO₂ C₁₋₄ alkyl, CN or, when n is2, X may also represent OH, SH or NH₂ ;

R⁶ is a hydrogen atom, a C₁₋₄ alkyl, (CH₂)_(m) cyclopropyl, --S(O)_(s)C₁₋₄ alkyl, phenyl, NR¹⁰ R¹¹, CH₂ C(O)CF₃, trifluoromethyl,difluoromethyl or cyano group;

R⁷ and R⁸ may each independently represent hydrogen atoms or a C₁₋₄alkyl group;

R⁹ represents a C₁₋₄ alkyl or trifluoromethyl group;

R¹⁰ and R¹¹ may each independently represent a hydrogen atom, or a C₁₋₄alkyl or acyl group;

x represents zero or 1;

n is 1 or 2;

s represents zero, 1 or 2;

m represents zero or 1;

p represents zero or 1;

and pharmaceutically acceptable salts and solvates thereof.

Suitable pharmaceutically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable organic or inorganic acids for example, hydrochlorides,hydrobromides, sulphates, alkyl- or arylsulphonates (e.g.methanesulphonates or p-toluenesulphonates), phosphates, acetates,citrates, succinates, tartrates, fumarates and maleates. Dihydrochloridesalts are particularly suitable.

Other acids, such as oxalic, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of formula (I) and theirpharmaceutically acceptable acid addition salts.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includesboth compounds of formula (I) and their pharmaceutically acceptable acidaddition salts together with pharmaceutically acceptable solvates.

It will be appreciated by those skilled in the art that the compounds offormula (I) contain at least two chiral centres (shown as * in formula(I)) and thus exist in the form of two pairs of optical isomers (i.e.enantiomers) and mixtures thereof including racemic mixtures.

For example the compounds of formula (I) may be either cis isomers, asrepresented by figures (a) and (b), or trans isomers, as represented byfigures (c) and (d), or mixtures thereof.

All of the isomers of the compounds of formula (I) represented by thefigures (a) to (d) and mixtures thereof including racemic mixtures areincluded within the scope of the invention. ##STR5##

The compounds of formula (I) are preferably in the form of their cisisomers (i.e. as represented by figures (a) and (b)). The 2S, 3S isomers(i.e. as represented by figure (b)) are particularly preferred.

Referring to the general formula (I), a C₁₋₄ alkoxy group may be astraight chain or branched chain alkoxy group, for example, methoxy,ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy or2-methylprop-2-oxy. A C₁₋₄ alkyl group may be a straight chain orbranched chain alkyl group and may be, for example, methyl, ethyl,propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-1-yl or2-methylprop-2-yl. An --O--(CH₂)_(p) C₃₋₇ -cycloalkyl group may be, forexample cyclopropyloxy, cyclopropylmethyloxy, cyclobutyloxy,cyclobutylmethyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy.

Referring to the general formula (I), an --O--C₁₋₇ fluoroalkyl group maycontain 1, 2 or 3 fluorine atoms and the C₁₋₇ alkyl chain may bestraight or branched. Examples of suitable groups includefluoromethyloxy, difluoromethyloxy, trifluoromethyloxy and2,2,2-trifluoroethyloxy.

Referring to the general formula (I), when R⁷, R⁸, or R⁹ represents aC₁₋₄ alkyl group, this is suitably methyl.

Referring to the general formula (I), a halogen atom may be a fluorine,chlorine, bromine or iodine atom, such as a fluorine, chlorine orbromine atom.

Referring to the general formula (I), R¹ is suitably --O--(CH₂)_(n) Xwhere X is suitably a group selected from C(O)NHMe, C(O)NH₂, C(O)NMe₂,C(O)Me, C(O)CF₃, NHMe, NMe₂, SO₂ NH₂, SO₂ NHMe, SO₂ NMe₂, NHSO₂ Me,NHSO₂ CF₃, S(O)_(s) Me or S(O)_(s) CF₃, for example where s is 2, OMe,NO₂, CO₂ H, CO₂ Me, CN or, when n is 2, X is suitably OH, SH or NH₂.

X is preferably OC₁₋₄ alkyl, for example OMe.

Referring to the general formula (I), R¹ is suitably a --O--(CH₂)_(p)-cyclopropyl, --O--(CH₂)_(p) -cyclopentyl, --O--C₁₋₄ fluoroalkyl orO--(CH₂)_(n) OC₁₋₄ alkyl group, such as cyclopropylmethyloxy,cyclopentyloxy, fluoromethyloxy, difluoromethyloxy, trifluoromethyloxy,2,2,2-trifluoroethyloxy, especially fluoromethyloxy, O--(CH₂)_(n) OMe,for example OCH₂ OMe or O--CH₂ CH₂ OMe.

Referring to the general formula (I), R² is suitably a group ##STR6##

Referring to the general formula (I), when R⁶ is an NR¹⁰ R¹¹ group; thisis suitably NH₂, NH(C₁₋₄ alkyl), NHacyl i.e. NHC(O)methyl, or N(C₁₋₄alkyl)₂.

Referring to the general formula (I), when R⁶ is a C₁₋₄ alkyl group,this is suitably methyl.

Referring to the general formula (I), when R² is a group (A) as definedabove, R⁶ is suitably a hydrogen atom or a C₁₋₄ alkyl, e.g. methyl, or atrifluoromethyl group.

R² is preferably a group (A) as defined above.

R³ is preferably a hydrogen atom.

R⁴ and R⁵ are preferably hydrogen atoms.

R⁶ is preferably a hydrogen atom, a C₁₋₄ alkyl, e.g. methyl, or atrifluoromethyl group.

x is preferably zero.

A preferred class of compounds of formula (I) are those wherein R¹ is--O--(CH₂)_(p) C₃₋₇ cycloalkyl or --O--C₁₋₇ fluoroalkyl, as definedhereinbefore, R² is ##STR7## where R⁶ is a hydrogen atom, a C₁₋₄ alkyl,e.g. methyl, or trifluoromethyl group, x is zero and R³, R⁴ and R⁵ areeach hydrogen atoms.

A further preferred class of compounds of formula (I) are those whereinR¹ is a cyclopropylmethoxy, cyclopentyloxy, difluoromethyloxy,trifluoromethyloxy, 2,2,2-trifluoroethyloxy or, more preferably, afluoromethyloxy group, R² is a group (A) as defined above, x is zero,R³, R⁴ and R⁵ are hydrogen atoms, and R⁶ is a hydrogen atom or a methylor trifluoromethyl group.

A preferred class of compounds of formula (I) are those wherein R¹ is agroup --O--(CH₂)_(n) X, R² is a group (A) as defined above, x is zeroand R⁶ is a hydrogen atom or a trifluoromethyl, difluoromethyl or cyanogroup.

An additional preferred class of compounds of formula (I) are thosewherein R¹ is --O--(CH₂)_(n) X where X is a group selected from C(O)NH₂,C(O)NHMe, C(O)NMe₂, C(O)Me, C(O)CF₃, NHMe, NMe₂, SO₂ NH₂, SO₂ NHMe, SO₂NMe₂, NHSO₂ Me, NHSO₂ CF₃, S(O)_(s) Me or S(O)_(s) CF₃, for examplewhere s is 2, OMe, NO₂, CO₂ H, CO₂ Me, CN or, when n is 2, X is OH, SHor NH₂, R² is a group (A) as defined above, x is zero, R⁶ istrifluoromethyl, and R³, R⁴ and R⁵ are each hydrogen atoms.

A further preferred class of compounds of formula (I) are those whereinR¹ is O--(CH₂)_(n) OC₁₋₄ alkyl, such as O--(CH₂)_(n) OMe, for exampleOCH₂ OMe or O--CH₂ CH₂ OMe, R² is a group (A) as defined above, x iszero, R³, R⁴ and R⁵ are hydrogen atoms, and R⁶ is trifluoromethyl.

Specific compounds according to the invention include:

(2-Cyclopentoxy-5-tetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Cyclopropylmethoxy-5-tetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Cyclopentoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidine-3-yl)amine;

(2-Cyclopropylmethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Fluoromethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

[2-(2-methoxy-1-ethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidine-3-yl)amine

and pharmaceutically acceptable salts, especially the dihydrochloridesalts, and solvates thereof.

Further specific compounds according to the invention include:

(2-Cyclopentoxy-5-(5-methyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Trifluoromethoxy-5-tetrazol-1-ylbenzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Trifluoromethoxy-5-5-methyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Trifluoromethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Difluoromethoxy-5-tetrazol-1-ylbenzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Difluoromethoxy-5-(5-methyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Difluoromethoxy-5-(5trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-(2,2,2-Trifluoroethoxy)-5-tetrazol-1-ylbenzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-(2,2,2-Trifluoroethoxy)-5-(5-methyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-(2,2,2-Trifluoroethoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

(2-Cyclopropylmethoxy-5-(5-methyltetrazol-1-yl)benzyl)-([2S,3S]-2-phenylpiperidin-3-yl)amine;

and pharmaceutically acceptable salts and solvates thereof.

The compounds of the invention are antagonists of tachykinins, includingsubstance P and other neurokinins both in vitro and in vivo and are thusof use in the treatment of conditions mediated by tachykinins, includingsubstance P and other neurokinins.

The compounds of the invention possess NK₁ - receptor binding affinityas determined in vitro by their ability to displace [3H]- substance P(SP) from recombinant human NK₁ receptors expressed in Chinese HamsterOvary (CHO) cell membranes. CHO membranes (3-5 μg protein per tube) wereprepared and incubated with [3H]-SP (0.6-0.8 nM) at 20° C. for 40 min.Non-specific binding was defined as that remaining in the presence of 1μM (+) CP99,994.

The compounds of the invention have been shown to have anti-emeticactivity as indicated by for example their ability to inhibitradiation-induced emesis in the ferret. In this model of emesis theonset of retching and vomiting occurs approximately 20 minutes afterwhole body irradiation (2 Grey.tbd.200 Rads). The test compound isadministered (e.g. i.p, p.o., i.v., s.c) immediately after irradiationand its effect on emesis determined by comparison with appropriatecontrols. Anti-emetic activity may also be demonstrated using otheremetogens such as cisplatin and ipecacuanha. Alternatively, the testcompounds may be administered before irradiation or before treatmentwith an emetogen, for example 1.5, 3 or 6 hours before irradiation.

The compounds of the invention are potent and specific NK₁ antagonists.Furthermore, they exhibit good oral bioavailability and have anadvantageous duration of action.

Compounds of the invention are useful as analgesics in particular theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica: angina; ankylosing spondyolitis; gout; bums; scar pain;itch; and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful as antiinflammatory agents inparticular they are useful in the treatment of inflammation in asthma,influenza, chronic bronchitis and rheumatoid arthritis: in the treatmentof inflammatory diseases of the gastrointestinal tract such as Crohn'sdisease, ulcerative colitis, inflammatory bowel disease, non-steroidalanti-inflammatory drug induced damage and inflammatory and secretoryeffects of bacterial infection, e.g. due to Clostridium difficile;inflammatory diseases of the skin such as herpes and eczema;inflammatory diseases of the bladder such as cystitis and urge (i.e.urinary) incontinence; and eye and dental inflammation, e.g. gingivitisand periodontitis.

Compounds of the invention are also useful in the treatment of allergicdisorders in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention may also be useful in the treatment of CNSdisorders in particular psychoses such as schizophrenia, mania ordementia; cognitive disorders e.g. Alzheimer's disease; anxiety; AIDSrelated dementia; diabetic neuropathy; multiple sclerosis; depression;Parkinson's disease; and dependency on drugs or substances of abuse; andalso the compounds of the invention may act as myorelaxants andantispasmodics.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed or late emesis and anticipatory emesis. The compounds of theinvention, are useful in the treatment of emesis however induced. Forexample, emesis may be induced by drugs such as cancer chemotherapeuticagents such as alkylating agents, e.g. cyclophosphamide, carmustine,lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin,doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g.cytarabine, methotrexate and 5- fluorouracil; vinca alkaloids, e.g.etoposide, vinblastine and vincristine; and others such as cisplatin,dacarbazine, procarbazine and hydroxyurea; and combinations thereof;radiation sickness; radiation therapy, e.g. irradiation of the thorax orabdomen, such as in the treatment of cancer; carcinoid syndrome;poisons; toxins such as toxins caused by metabolic disorders or byinfection, e.g. gastritis, or released during bacterial or viralgastrointestinal infection; pregnancy; vestibular disorders, such asmotion sickness, vertigo, dizziness and Meniere's disease.post-operative sickness; dialysis-induced emesis; prostaglandin-inducedemesis; gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine;gastro-oesophageal reflux disease, acid indigestion, over-indulgence offood or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn and dyspepsia; organ failure, such as in terminalillness; AIDS and AIDS-related conditions, and treatments thereof; andcyclic vomiting syndrome.

Compounds of the invention are also useful in the treatment ofgastrointestinal disorders such as irritable bowel syndrome; skindisorders such as psoriasis, pruritis and sunburn; vasospastic diseasessuch as angina, vascular headache and Reynaud's disease; cerebralischeamia such as cerebral vasospasm following subarachnoid haemorrhage;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders related to immune enhancement or suppressionsuch as systemic lupus erythematosus and rheumatic diseases such asfibrositis; and cough.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins, comprising administration of an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), transdermal, depotor rectal administration or in a form suitable for administration byinhalation or insufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parentera:administration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

For transdermal administration the compounds according to the inventionmay be formulated as creams, gels, ointments or lotions or as atransdermal patch. Such compositions may for example be formulated withan aqueous or oily base with the addition of suitable thickening,gelling, emulsifying, stabilising, dispersing, suspending, and/orcolouring agents.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunit dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

The compositions may contain from 0.1% upwards, e.g. 0.1-99% of theactive material, depending on the method of administration. A proposeddose of the compounds of the invention is 0.05 mg/kg to about 400 mg/kgbodyweight per day e.g. 0.05 mg/kg to 5 mg/kg per day. It will beappreciated that it may be necessary to make routine variations to thedosage, depending on the age and condition of the patient and theprecise dosage will be ultimately at the discretion of the attendantphysician or veterinarian. The dosage will also depend on the route ofadministration and the particular compound selected.

The compounds of formula (I) may, if desired, be administered with oneor more therapeutic agents and formulated for administration by anyconvenient route in a conventional manner. Appropriate doses will bereadily appreciated by those skilled in the art. For example, thecompounds of formula (I) may be administered in combination with asystematic anti-inflammatory corticosteroid such as methyl prednisoloneor dexamethasone, or a 5HT₃ antagonist such as ondansetron, granisetronor metoclopramide. The compounds of formula (I) may also be administeredin combination with sympathomimetics, such as ephedrine, pseudoephedrineand oxymetazoline, or the compounds may be administered withconventional analgesics, such as non-steroidal antiinflammatory drugs(NSAIDs), opioids or local anaesthetics. Compounds which are specificantagonists at NK₁ receptors, such as the compounds of formula (I), maybe administered in combination with compounds which are specificantagonists at NK₂ receptors.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R¹, R², R³, R⁴ and R⁵ and x are as previouslydefined for compounds of formula (I) unless otherwise stated.

According to a first general process (A), a compound of formula (I) maybe prepared by reacting a compound of formula (II): ##STR8## with acompound of formula (III) ##STR9## to form the intermediate imine, whichmay be isolated if required, followed by reduction of the imine using asuitable reducing agent such as a metal hydride, for example a boranehydride, alane hydride or a metal hydride complex like lithium aluminumhydride or sodium borohydride, or an organo-metallic complex such asborane- methyl sulphide, 9-borabicyclononane (9-BBN), triethylsilane,sodium triacetoxyborohydride, sodium cyanobarohydride and the like.Alternatively, catalytic hydrogenation may be used, for example using aplatinum catalyst in a suitable solvent e.g. ethanol.

The condensation reaction conveniently takes place in a suitable solventsuch as an alcohol (e.g. methanol), an aromatic hydrocarbon (e.g.benzene, toluene or xylene) or a chlorinated hydrocarbon (e.g.dichloromethane or dichloroethane) at a temperature ranging from ambientto the reflux temperature of the reaction mixture. The reactionpreferably takes place in the presence of a catalytic amount of asuitable acidic condensing agent such as p-toluenesulphonic acid oracetic acid and/or a dehydrating agent such as molecular sieves, or thereaction may take place under Dean-Stark conditions.

The reduction step conveniently takes place in a suitable solvent suchas acetonitrile, dimethylformamide, benzene, chlorinated hydrocarbonssuch as dichloromethane or dichloroethane, ethers such as diethyl ether,tetrahydrofuran, dioxane and 1,2-dimethoxyethane and alcohols such asethanol at a temperature ranging from 0° C. to the reflux temperature ofthe reaction mixture.

Process (A) may also take place in one step without isolation of theintermediate imine if the condensation reaction takes place in thepresence of sodium cyanoborohydride or sodium triacetoxyborohydride.Further reduction is therefore unnecessary in this case.

When carrying out process (A) where R² is a group (C) as definedhereinbefore, R⁶ is preferably a C₁₋₄ alkyl group.

Compounds of formula (II) may be prepared by reducing compounds offormula (IV) ##STR10## under suitable reducing conditions, such ascatalytic hydrogenation, for example using a platinum catalyst, e.g.platinum (IV) oxide, in a suitable solvent like ethanol, preferably inthe presence of concentrated hydrochloric acid.

Compounds of formula (IV) may be prepared by reacting2-chloro-3-nitropyridine with a compound of formula (V) ##STR11## in thepresence of a palladium (O) catalyst such as tetrakis (triphenylphosphine) palladium (O). The reaction suitably takes place in thepresence of a solvent such as an ether, e.g. dimethoxyethane, at anelevated temperature and preferably in the presence of a base such assodium carbonate.

Compounds of formula (V) may be prepared by reacting the correspondingbromo-compounds under Grignard conditions followed by reaction withtri-isopropylborate.

Alternatively, compounds of formula (II) may be prepared by reducingcompounds of formula (VI) ##STR12## under suitable reducing conditions,for example using a metal hydride complex such as sodium borohydride inthe presence of zirconium (IV) chloride in a suitable solvent such astetrahydrofuran.

Compounds of formula (VI) may be prepared by reacting compounds offormula (VII) ##STR13## with hydroxylamine hydrochloride in the presenceof pyridine.

Compounds of formula (VII) may be prepared by reacting compounds offormula (VIII) ##STR14## with ozone in the presence of potassiumt-butoxide in a suitable solvent such as a mixture of dichloromethaneand methanol.

Compounds of formula (VII) may be prepared by reacting compounds offormula (IX) ##STR15## with methyl-4-nitrobutyrate and ammonium acetate,in a suitable solvent such as an alcohol, e.g. ethanol at elevatedtemperature.

Compounds of formula (III), except where R¹ represents cyclopropyloxy,cyclobutyloxy or trifluoromethyloxy, may be prepared by reactingcompounds of formula (X) ##STR16## with an appropriate alkylating agent,such as (CH₂)_(p) C₃₋₇ cycloalkyl bromide or iodide or C₁₋₇ fluoroalkylchloride, bromide or iodide, in the presence of a base such as potassiumcarbonate.

Compounds of formula (III) where R¹ represents 2,2,2-trifluoroethyloxymay be prepared by reacting compounds of formula (X) with CF₃ CH₂ OSO₂R^(a), where R^(a) represents methyl, paratoluyl or trifluoromethyl, inthe presence of hexamethylphosphoramide and potassium carbonate atelevated temperature.

Compounds of formula (III) where R¹ represents trifluoromethyloxy may beprepared by reacting compounds of formula (X), or a protected aldehydethereof, with carbondisulphide and methyl iodide to give the xanthatederivative. The xanthate derivative is then treated withhydrogenfluoride-pyridine complex and deprotected if necessary, to givethe required compound of formula (III).

Compounds of formula (III) where R¹ represents cyclopropyioxy may beprepared by reacting compounds of formula (X), or a protected aldehydethereof, with ethylvinyl ether in the presence of mercury acetate. Theresulting vinyl derivative is treated with diiodomethane and diethylzincand deprotected if necessary, to give the required compound of formula(III).

Compounds of formula (III) where R¹ represents cyclobutyloxy may beprepared by reacting compounds of formula (XI) ##STR17## where R^(b) isa suitable leaving group, such as CF₃ SO₃, or a protected aldehydethereof, with cyclobutanol in the presence of a base, such as sodiumhydride, and a solvent such as dimethylformamide, followed bydeprotection where necessary.

Compounds of formula (XI) may be prepared by conventional methods. Forexample, compounds of formula (XI) where R^(b) is CF₃ SO₃ may beprepared by reacting compounds of formula (X) withtrifluoromethanesulphonic anhydride in the presence of a base, such astriethylamine.

Compounds of formula (X) may be prepared by reacting compounds offormula (XII) ##STR18## with hexamethylenetetramine in the presence oftrifluoroacetic acid at elevated temperature.

Compounds of formula (XII) where R² is a group (A) as define,hereinbefore and x is zero may be prepared by reacting the appropriatep-hydroxyaniline, or a protected derivative thereof, with compounds offormula (XIII)

    R.sup.6 --C(OR.sup.9).sub.3                                (XIII)

(where R⁹ is methyl or ethyl), for example triethylorthoacetate, inacetic acid followed by reaction with sodium azide at elevatedtemperature and deprotection if necessary.

Compounds of formula (XII) where R² is a group (A) as definedhereinbefore and x is zero may also be prepared by reacting a compoundof formula (XIV) ##STR19## or a protected derivative thereof, withsodium azide in acetic acid at elevated temperature, followed bydeprotection if necessary.

Compounds of formula (XIV) may be prepared by reacting a compound offormula (XV) ##STR20## or a protected derivative thereof, withresin-supported triphenylphosphine in carbon tetrachloride at elevatedtemperature.

Compounds of formula (XV) may be prepared by reacting the appropriatep-hydroxyaniline, or a protected derivative thereof, with theappropriate acid chloride or anhydride, i.e. R⁶ --COCl or R⁶--CO.O.CO--R⁶, for example trifluoroacetic anhydride, cyclopropanecarbonyl chloride, or difluoroacetic anhydride (or the activated acidmay be prepared in situ from difluroacetic acid and e.g.dicyclohexylcarbodiimide).

Compounds of formula (XII) where R² is a group (A) as definedhereinbefore and x is zero, or protected derivatives thereof, mayalternatively be prepared by reacting compounds of formula (XV), orprotected derivatives thereof, with an acid anhydride such astrifluoroacetic anhydride or trifluoromethane sulfonic anhydride andsodium azide in acetonitrile.

Compounds of formula (III) where R² is a group (A) as definedhereinbefore, x is zero and R⁶ is --NH₂ may alternatively be prepared byreacting compounds of formula (XVI) ##STR21## or a protected derivativethereof, with ammonium chloride and sodium azide at elevatedtemperature, suitably in a solvent such as dimethylformamide, followedby deprotection where required.

Compounds of formula (XVI) may be prepared by reacting compounds offormula (III) where R² is a group (A) as defined hereinbefore, x is zeroand R⁶ is hydrogen, or a protected derivative thereof, with n-butyllithium in a suitable solvent such as tetrahydrofuran.

Compounds of formula (III), or protected derivatives thereof, where R⁶represents one group may be converted into other compounds of formula(III), or protected derivatives thereof, where R⁶ represents a differentgroup using conventional procedures, such as alkylation, acylation oroxidation.

Compounds of formula (III) may alternatively be prepared by oxidisingcompounds of formula (XVII) ##STR22## with a suitable oxidising agentsuch as manganese dioxide in a suitable solvent such as an ether, e.g.tetrahydrofuran, at elevated temperature.

Compounds of formula (XVII), except where R⁶ is a cyano group, may beprepared by reducing compounds of formula (XVIII) ##STR23## with asuitable reducing agent such as a metal hydride complex such as lithiumborohydride in a suitable solvent such as an ether, e.g.tetrahydrofuran, or an alcohol, e.g. ethanol, or a mixture thereof.

Compounds of formula (XVIII) where R² is a group (A) as definedhereinbefore and x is zero may be prepared from the corresponding2-alkoxy-5-amino benzoic acid methyl ester by reacting with compounds offormula (XIII) as defined above, e.g. triethyl orthoformate, and sodiumazide in glacial acetic acid and dimethylform-amide at elevatedtemperature.

Suitable 2-alkoxy-5-amino benzoic acid methyl esters are either known ormay be prepared according to methods known for the preparation of knowncompounds e.g. the method described by Bergman et al in Can.J.Chem,(1973), 51, 162-70.

Compounds of formula (III) where R² is a group (A) or (B) as definedhereinbefore and x is 1, may be prepared by reacting compounds offormula (XIX) ##STR24## (where hal is a halogen, e.g. bromine orchlorine, atom) with tetrazole in the presence of a base such astriethylamine or potassium carbonate in a suitable solvent such asdichloromethane or dimethylformamide.

Compounds of formula (XIX) where x is 1 may be prepared by reactingcompounds of formula (XX) ##STR25## or a protected derivative thereof,with a carbon tetrahalide, e.g. carbon tetrabromide, in the presence oftriphenylphosphine and a suitable solvent such as ether, followed bydeprotection where required.

Compounds of formula (XX) may be prepared by reduction of thecorresponding aldehydes after protection of the aldehyde group ortho toR¹.

Compounds of formula (XII) where R² is a group (B) and x is zero may beprepared by reacting the appropriate 1-fluoro-4-nitrobenzene withIH-tetrazole in a suitable solvent at elevated temperature, followed byreduction of the nitro group by catalytic hydrogenation, followed byconversion of the resulting amino function into an alcohol functionusing nitrous acid.

Compounds of formula (III) where R² is a group (C) as definedhereinbefore may be prepared by reacting a compound of formula (XXI)##STR26## with a compound of formula (XXII) ##STR27## in the presence ofa palladium (O) catalyst such as tetrakis (triphenylphosphine) palladium(O) in a suitable solvent such as an ether (e.g. dimethoxyethane) at anelevated temperature.

Compounds of formula (XXI) may be prepared according to similar methodsfor the preparation of compounds of formula (V) above.

Alternatively, compounds of formula (III) where R² is a group (C) asdefined hereinbefore, x is zero and R⁶ is hydrogen may be prepared byreacting compounds of formula (XXIII) ##STR28## or a protectedderivative thereof, with tributyltinazide at elevated temperature,followed by deprotection where necessary.

Compounds of formula (XXIII) may be prepared from the appropriatep-hydroxybenzonitrile and hexamethylenetetramine as described above forthe preparation of compounds of formula (X) from compounds (XII).

According to a further general process (B), compounds of formula (I)where R² is a group (A) as defined hereinbefore, x is zero and R⁶ is--NH₂ may be prepared by reacting compounds of formula (XXIV) ##STR29##with ammonium chloride and sodium azide under conditions as describedabove for the preparation of compounds of formula (III) from compoundsof formula (XVI).

Compounds of formula (XXIV) may be prepared by reacting compounds offormula (XVI) with compounds of formula (III) under conditions asdescribed above for process (A).

According to a further general process (C), compounds of formula (I) maybe prepared by reduction of compounds of formula (XXV) ##STR30## with asuitable reducing agent, such as a metal hydride, for example a boranehydride, in a suitable solvent such as an ether, e.g. tetrahydrofuran,at ambient temperature.

Compounds of formula (XXV) may be prepared by reacting compounds offormula (III) with compounds of formula (XXVI) ##STR31## underconditions as described above for process (A).

Compounds of formula (XXVI) are either known or may be preparedaccording to methods known for the preparation of known compounds, forexample according to the method described in European Patent ApplicationNo. EP-A-0436334, incorporated herein by reference.

According to a further general process (D) compounds of formula (I),excluding compounds where R¹ represents cyclopropyloxy, cyclobutyloxyand trifluoromethyloxy, may be prepared by reacting a compound offormula (XXVII) ##STR32## or an amino-protected derivative thereof, withL--(CH₂)_(p) C₃₋₇ cycloalkyl or L--C₁₋₇ fluoroalkyl where p is asdefined hereinbefore and L represents a suitable leaving group such asiodine, bromine, chlorine, OSO₂ R^(c) ₁ where R^(c) represents methyl,paratoluyl or trifluoromethyl, in the presence of a base, such aspotassium carbonate, and a suitable solvent, such as dimethylformamide,at a temperature between 0 and 100° C., e.g. at room temperature,followed by deprotection where necessary.

Compounds of formula (XXVII) may be prepared by reacting compounds offormula (XXVIII) ##STR33## where R¹⁰ is C₁₋₄ alkyl, e.g. methyl, withborane-methyl sulphide complex in a suitable solvent, such asdichloromethane, at elevated temperature.

Compounds of formula (XXVIII) may be prepared according to similarmethods described herein for the preparation of compounds of formula (I)and those methods described in PCT patent application no.PCT/EP94/03129.

According to a further general process (E) compounds of formula (I)where R² is a group A as defined above and R⁶ represents cyano may beprepared by reacting a compound of formula (XXIX) ##STR34## where Lrepresents a suitable leaving group, such as a methylsulphonyl group,with potassium cyanide. The reaction conveniently takes place atelevated temperature and in the presence of a suitable solvent, such asan alcohol, e.g. ethanol.

Compounds of formula (XXIX) may be prepared by the methods described inprocesses (A) to (D) described hereinbefore from the appropriatelysubstituted intermediates and also from those methods described in PCTparent application no. PCT/EP94/03129.

Suitable protecting groups for the hydroxyl function include benzylgroups which may be introduced and removed according to conventionalprocedures. For example deprotection may be effected by catalytichydrogenation.

Aldehyde functions may be protected as acetals which may be introducedand removed according to conventional procedures. For example,deprotection may be effected by acid hydrolysis.

Amino functions may be protected by, for example, a t-butyl carbamate(BOC) group or a benzyl group which may be introduced and removedaccording to conventional procedures. For example, deprotection of BOCgroups may be effected by acid hydrolysis.

Compounds of formulae (III), (XVI), (XVII), (XVIII), (XXIV), (XXV),(XXVII) and (XXIX) are novel and therefore form a further feature of theinvention.

Where it is desired to isolate a compound of formula (I) as a salt, forexample a pharmaceutically acceptable salt, this may be achieved byreacting the compound of formula (I) in the form of the free base withan appropriate amount of suitable acid and in a suitable solvent such asan alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) oran ether (e.g. diethyl ether or tetrahydrofuran).

Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation from or evaporation of anappropriate solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods.

Thus, in one example an appropriate optically active acid may be used toform salts with the enantiomeric mixture of a compound of generalformula (I). The resulting mixture of isomeric salts may be separatedfor example by fractional crystallisation, into the diastereoisomericsalts from which the required enantiomer of a compound of generalformula (I) may be isolated by conversion into the required free base.

Alternatively, enantiomers of a compound of general formula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

A particularly suitable route for the preparation of optically activeintermediates of formula (II) from the enantiomeric mixture thereof isby fractional crystallisation using (2R,3R)-bis-(4methyl-benzoyloxy)-succinic acid. Thus, the cis (S,S) form ofintermediate (II) may be obtained from an enantiomeric mixture thereof(e.g. the racemic mixture) by fractional crystallisation with (2R,3R)-bis-4-methyl-benzoyloxy)-succinic acid in a suitable solvent, suchas an aqueous alcohol, e.g. aqueous ethanol, isolating the resultingsalt and converting it into the corresponding optically active free baseby conventional procedures for example using aqueous ammonia.

Alternative methods for preparing and resolving2-phenyl-3-aminopiperidine are described in PCT patent application no.WO 94/27966, incorporated herein by reference.

Specific enantiomers of a compound of formula (I) may also be obtainedby chromatography of the corresponding enantiomeric mixture on a chiralcolumn, for example by chiral preparative h.p.l.c.

Specific diastereoisomers of a compound of general formula (I) may beobtained by conventional methods for example, by synthesis from anappropriate asymmetric starting material using any of the processesdescribed herein, or by conversion of a mixture of isomers of a compoundof general formula (I) into appropriate diastereoisomeric derivativese.g. salts which can then be separated by conventional means e.g. bychromatography or by fractional crystallisation. Alternatively, thediastereosiomers may be separable without the need for furtherderivatization.

Standard resolving methods are described for example in `Steidochemistryof Carbon Compounds` by E. L. Eliel (McGraw Hill, 1962) and `Tables ofResolving Agents` by S. H. Wilen.

The various general methods described above may be useful for theintroduction of the desired groups at any stage in the stepwiseformation of the required compound, and it will be appreciated thatthese general methods can be combined in different ways in suchmulti-stage processes. The sequence of the reactions in multi-stageprocesses should of course be chosen so that the reaction conditionsused do not affect groups in the molecule which are desired in the finalproduct.

The invention is further illustrated by the following Intermediates andExamples which are not intended as a limitation of the invention. Alltemperatures are in ° C. Flash column chromatography (FCC) was carriedout on silica (Merck 3385). The following abbreviations are used:ether-diethyl ether.

Intermediate 1

4-Tetrazol-1-yl-phenol

To a stirred solution of p-amino-phenol (0.1 mol) in glacial acetic acid(140 ml) at 70-75° under nitrogen atmosphere was addedtriethylorthoformate (0.1 mol). The mixture was stirred at thistemperature for 4 h, then, sodium azide (0.32 mol) was added portionwiseand the reaction was continued for 18 h, cooled to room temperature andpoured into ice water (400 ml) and extracted with diethyl ether (3×400ml) and ethyl acetate (1×400 ml), dried (MgSO₄), filtered andconcentrated to give a dark brown residue which was triturated with 200ml of a mixture of ethanol:diethyl ether (1:1 v/v) and filtered toafford the title compound in 30% yield.

T.I.c. (ether) Rf 0.65

Intermediate 2

2-Hydroxy-5-tetrazol-1-yl-benzaldehyde

A solution of 4-tetrazol-1-yl-phenol (0.01 mol) in trifluoroacetic acid(20 ml) and hexamethylenetetramine (0.04 mol) was heated at 70° for 18h, cooled to room temperature and quenched with 2N solution of sulfuricacid (50 ml). The mixture was extracted with ethyl acetate (3×100 ml),dried (MgSO₄), filtered and concentrated to give a residue which waspurified by FCC (dichloromethane/methanol (9:1)) to afford the titlecompound in 30% yield.

T.l.c. (dichloromethanelmethanol (9:1)) Rf 0.6

Intermediate 3

2-Cyclopentoxy-5-tetrazol-1-ylbenzaldehyde

A mixture of 2-hydroxy-5tetrazol-1-yl-benzaldehyde (500 mg) andpotassium carbonate (431 mg) in dimethylformamide (5 ml) at 20° wastreated with cyclopentyl bromide (0.33 ml). After 24 h water (20 ml) wasadded and the mixture extracted with ethyl acetate (2×25 ml). Theorganics were washed with water (25 ml) and brine (25 ml) and dried (Na₂SO₄). Evaporation gave a yellow solid which was purified by FCC (ethylacetate/cyclohexane (2:1)) to give the title compound, as a yellow solid(334 mg).

ν_(max) (KBr) 1677 cm⁻¹

Similarly prepared:

Intermediate 4

2-Cyclopropylmethoxy-5-tetrazol-1-ylbenzaldehyde

From cyclopropyl methyl bromide (0.3 ml) to give the title compound, asa white solid (164 mg).

ν_(max) (KBr) 1681 cm⁻¹

Intermediate 5

N-(4-Benzyloxy-phenyl)-2,2,2-trifluoro-acetamide

A mixture of 4-benzyloxyaniline hydrochloride (0.19 mol) indichloromethane (750 ml) at 0° under nitrogen was treated dropwise withtrifluoroacetic anhydride (27.6 ml) then triethylamine (60 ml) After 24h the mixture was poured into t-butyl methyl ether (1.5 l) and waswashed with 2N hydrochloric acid (11). The organic phase was dried(MgSO₄) and evaporated in vacuo to give the title compound as a whitesolid (52.3 g).

T.l.c. (cyclohexanelethylacetate (9:1)) Rf 0.36.

Intermediate 6

(4-Benzyloxy-phenyl)-(1-chloro-2,2,2-trifluoro-ethylidene)-amine

A mixture of resin-supported triphenylphosphine (3 mmoltriphenylphosphine/g resin; 58.6 g) andN-(4-benzyloxy-phenyl)-2,2,2-trifluoro-acetamide (20.8 g) in carbontetrachloride (800 ml) was heated to reflux under nitrogen for 18 h. Themixture was allowed to cool then filtered, washing the resin withdichloromethane (1 l) and ether (1 l). The organics were concentrated invacuo to give the title compound as a yellow solid (20.7 g).

T.l.c. (Cyclohexane/ethyl acetate (9:1)) Rf 0.81

Intermediate 7

1-(4-Benzyloxy-phenyl)-5-trifluoromethyl-1 H-tetrazole

(4-Benzyloxy-phenyl)-(1-chloro-2,2,2-trifluoro-ethylidene)-amine (66mmol) was added to a stirred flask of glacial acetic acid (250 ml) at70° under nitrogen. After 4 min sodium azide (210 mmol) was added andheating was continued for 3 h. After cooling the mixture was filtered,the filtrate poured into water (750 ml) then extracted withdichloromethane (500 ml ×3). The combined organic extracts were dried(Na₂ SO₄) and evaporated in vacuo. Purification by FCC usinghexane-ethyl acetate (19:1) gave the title compound as a white solid(14.5 g).

T.l.c. (Cyclohexane/ethyl acetate (19:1) Rf 0.22

Intermediate 8

4-(5-Trifluoromethyl-tetrazol-1-yl)-phenol

A solution of 1(4-benzyloxy-phenyl)-5-trifluoromethyl-1H-tetrazole (45.3mmol) in ethanol (100 ml) and tetrahydrofuran (100 ml) was hydrogenatedat room temperature and atmospheric pressure over 10% palladium-carboncatalyst (6 g). After 2 h, the mixture was filtered and the filtrate wasevaporated to give the title compound (10.4 g) as a cream solid.

T.I.c. (Dichlormethanelethanol/ammonia(200:8:1)) Rf 0.3.

Intermediate 9

2-Hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde

A solution of 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol (45 mmol) intrifluoroacetic acid (200 ml) and hexamethylenetetramine (186.9 mmol)was heated at 100° under nitrogen for 16 h. The reaction mixture wasquenched with 2N sulphuric acid (250 ml) and extracted with ether (3×250ml)). The combined organics were dried (Na₂ SO₄) and evaporated to givea dark yellow oil. Purification by FCC (hexane/ether (2:1)) afforded thetitle compound (8.8 g) as a pale yellow solid.

T.l.c. (hexane/ether (2:1)) Rf 0.36

Intermediate 10

2-Methoxy-5-(5-trifluoromethyl-etrazol-1-yl)-benzaldehyde

A mixture of 2-hydroxy-5-(5trifluoromethyl-tetrazol-1-yl)-benzaldehyde(1.56 mmol), potassium carbonate (7.8 mmol) and methyl iodide (7.8mmol), in acetone (25 ml ) was stirred for 18 h at 23° under nitrogen.Water (150 ml) was added and the mixture extracted with diethyl ether(3×50 ml). The combined organic extracts were washed with saturatedbrine, dried (Na₂ SO₄) and evaporated to give the title compound as ayellow solid (0.48 g).

T.l.c. (ether/hexane (2:1)) Rf 0.38.

Intermediate 11

[2-Methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenyl-piperidine-3-yl)-aminedihydrochloride

A mixture of [2S]-phenyl-piperidin -[3S]-ylamine (1.14 mmol),2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde (1.2 mmol),sodium triacetoxyborohydride (2.37 mmol) and acetic acid (3 drops) indichloromethane (25 ml) was stirred at 23° under nitrogen for 64 h. 2Nsodium carbonate solution (50 ml) was added and the mixture extractedwith dichloromethane (3×25 ml). The combined extracts were washed withsaturated brine (50 ml), dried (MgSO₄) and evaporated. Purification byFCC with dichloromethane/ethanol/ammonia (400:10:1→100:10:1) gave acolourless viscous oil. This was dissolved in methanol (10 ml) andtreated with 2N ethereal hydrogen chloride (˜10 ml). Evaporation invacuo and trituration with i-propyl acetate gave the title compound as awhite solid (210 mg).

T.l.c. (Dichloromethanetethanol/ammonia (200:10:1)) Rf 0.39.

Optical Rotation (c 3 mg/ml. water) +50.35°.

Intermediate 12

[2-Hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidin-3-yl)amine

A suspension of[2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidin-3yi)aminedihydrochloride (1.01 g, 2 mmol) in chloroform (20ml) was stirred atroom temperature and treated with triethylamine, (0.58 ml, 406 mg, 4mmol) to give a clear solution. This was then treated slowly with asolution of boron tribromide: dimethylsulfide complex (20 ml of 1Msolution in dichloromethane; 20 mmol) and the reaction mixture wasrefluxed under nitrogen for 3 days. Further reagent (10 ml, 10 mmol) wasthen added and after a further 3 days the mixture was cooled in anice-bath, stirred and treated with methanol (40 ml ). The mixture wasevaporated to dryness. This treatment was repeated twice further. Theresulting oil was partitioned between ethyl acetate (100 ml) andsaturated aqueous sodium bicarbonate (100 ml). The aqueous phase wasextracted with further ethyl acetate (50 ml) after pH adjustment (to pHca 8). Combined extracts were washed with brine (100 ml) dried (MgSO₄)and evaporated to a brown foam, which was chromatographed on silica(Merck 9385) eluting with 2% then 5% methanol in dichloromethane. Therequired fractions were combined and evaporated to give the titlecompound as a light brown foam (672 mg), mass spectrum (thermospray +ve)m/e 419 (MH⁺).

Intermediate 13

3-{tert-Butoxycarbonyl-[2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-amino}-[2S,3S]-2-phenylpiperidine-1-carboxylicacid tert-butyl ester

A solution of[2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidine-3-yl)amine(418 mg, 1 mmol) in dichloromethane (5 ml) was treated withdi-t-butyidicarbonate (240 mg, 1.1 mmol) and the solution was stirredfor 19 h at room temperature. Further reagent was then added (240 mg)and after a further day the solution was evaporated to dryness. Theresulting gum was chromatographed on silica (Merck 9385; 70 g) elutingwith 3:1 then 1:1 cyclohexane:ethyl acetate. The required fractions werecombined and evaporated to provide the title compound as a light brownfoam (487 mg), ν(CHBr₃) 1663 and 1690cm⁻¹ (carbamate C═O).

Intermediate 14

3-{tert-Butoxycarbonyl-[2-(cyclopropylmethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-amino-}[2S,3S]-2-phenylpiperidine-1-carboxylicacid tert-butyl ester

A solution of3-{tert-butoxycarbonyl-[2-hydroxy-5-5trifluoromethyl-tetrazol-1-yl)-benzyl]-amino)}-[2S,3S]-2-phenylpiperidine-1-carboxylicacid tert-butyl ester (402 mg) in dimethylformamide (1 ml) containing asuspension of finely ground potassium carbonate (89 mg) was stirred atroom temperature and treated with cyclopropylmethyl bromide (529 mg).After 11 days stirring at room temperature the mixture was partitionedbetween ethyl acetate (50 ml) and 2M hydrochloric acid (50 ml). Theorganic phase was washed with brine (2×50 ml), dried (MgSO₄) andevaporated to give a brown gum. This was chromatographed on silica(Merck 9385) eluting with 7:1 then 5:1 cyclohexane:ethyl acetate to givethe title compound as a white foam (104 mg), mass spectrum (electrospray+ve) m/e 673. (MH⁺).

Intermediate 15

[2-(Fluoromethoxy)-5-(5trifluoromethyl-tetrazol-1-yl)]-benzaldehyde

A solution of[2-hydroxy-5-(5-trifluoromethyl)-tetrazol-1-yl)]-benzaldehyde (200 mg,0.77 mmole) in dimethylformamide (1 ml) containing a suspension ofpotassium carbonate (107 mg, 0.77 mmol) was stirred in an ice-bath andtreated with bromofluoromethane (few mls). Further bromofluoromethane(few mls) was added after 1.5 h and the reaction mixture was allowed toreach room temperature. After 17 h it was partitioned between ethylacetate (50 ml) and 2M-hydrochloric acid (50 ml) and brine (2×50 ml),dried (MgSO₄) and evaporated to the title compound as an off-white solid(211 mg), ν (CHBr₃) 1698 cm⁻¹ (C═O aldehyde).

Similarly prepared:

Intermediate 16

[2-(2-Cyclopentoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)]-benzaldehyde

From [2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)]-benzaldehyde (250mg, 0.97 mmole) and bromocyclopentane (434 mg, 2.91 mmole) to give thetitle compound as a pale yellow solid (240 mg), ν (KBr powder) 1687 cm⁻¹(C═O aldehyde).

EXAMPLE 1 (2-Cyclopentoxy-5-tetrazol-1-ylbenzyl)-([2S,3S]-2-phenylpiperidin-3-yl) amine dihydrochloride

To a solution of [2S]-phenylpiperidin-[3S]-ylamine (1.0 mmol) and2-cyclopentoxy-5-tetrazol-1-ylbenzaldehyde (0.91 mmol) indichloromethane (4 ml) and acetic acid (1.5 mmol), triacetoxyborohydride(1.30 mmol) was added. After 18 h the solvent was reduced and theresidue partitioned between ethyl acetate (25 ml) and 2M sodiumcarbonate solution (25 ml). The aqueous was re-extracted with ethylacetate (2×25 ml) and the combined organics dried (Na₂ SO₄) and reducedto an oil. This was dissolved in hot ethanol (8 ml) and conc.HCl added(177 μl). After 4 h the crystals' were harvested and dried in vacuo at50° overnight to give the title compound (309 mg).

δ(D₂ 0) 1.50-1.80 (6H, m), 1.80-2.00 (2H, m), 2.10-2.20 (2H, m), 2.30(1H, m) 2.55 (1H, m), 3.35 (1H, m), 3.75 (1H, m), 4.00 (1H, m), 4.15(1H, d J=18H_(z)), 4.40 (1H, d J=18H_(z)), 4.95 (1H, d J=5H_(z)), 7.15(3H, m), 7.40 (3H, m), 7.64 (1H, d J=4H_(z)), 7.80 (1H, dd J=11,4H_(z)), 9.58 (1 H, s).

Assay: Found: C.58.12%; H. 6.34%; N, 17.28%; Cl, 14.1%. C₂₄ H₃₀ N₆ O.2HCl requires C. 58.65%; H, 6.56%; N, 17.10%; Cl, 14.4%.

Similarly prepared:

EXAMPLE 2 (2-Cyclopropylmethoxy-5-tetrazol-1-ylbenzyl)-([2S,3S]-2-phenylpiperidin-3-yl) amine dichydrochloride

From 2-cyclopropylmethoxy-5tetrazol-1-ylbenzaldehyde (0.59 mmol) and[2S]-phenylpiperidin-[3S]-ylamine (0.65 mmol) to give the title compound(134 mg).

δ(D₂ O ) 0.30 (2H, m), 0.65 (2H, m), 1.20 (1H, m), 2.00-2.60 (4H, m),3.35(1 H, m), 3.65-3.90 (3H, m), 4.02 (1H, m), 4.21 (1H, d J=18H_(z)),4.45 (1H, d J =18H_(z)) 4.98 (1H, d J=5H_(z)), 7.15 (1H, d J=12H_(z)),7.25 (2H, m), 7.45 (3H, m), 7.62 (1H, m), 7.82 (1 H, dd J=11, 4H_(z)),9.57 (1 H, s).

Assay: Found: C, 57.70%; H, 6.32%; N, 17.43%, Cl, 14.7%. C₂₃ H₂₈ N₆O.2HCl requires

C, 57.86%; H, 6.33%; N,17.60%; Cl, 14.9%.

EXAMPLE 3[2(CycloPropylmethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidin-3-yl)amine dihydrochloride

A solution of3-{tert-butoxycarbonyl-[2-(cyclopropylmethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-amino}[2S,3S]-2-phenylpiperidine-1-carboxylicacid tertbutyl ester (101 mg, 0.15 mmole) in 4M-hydrogen chloride indioxan (5 ml) was kept at 44° for 3.25 h and then evaporated. Theresidue was triturated with ethanol to give the title compound as awhite solid (66 mg), mass spectrum (thermospray +ve) m/e 473 (MH⁺).R_(F) 0.5 (100: 8:1 dichloromethane: ethanol: ammonia).

EXAMPLE 4[2-(Fluoromethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylriperidin-3-yl)aminedihydrochloride

A suspension of ([2S, 3S]-2-phenylpiperidin-3-yl)amine dihydrochloride(90 mg, 0.36 mmole) in dichloromethane (2 ml) containing[2-(fluoromethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)]-benzaldehyde(104 mg, 0.36 mmole) was stirred at room temperature and treated withtriethylamine (73 mg, 0.72 mmole) to give a solution. Glacial aceticacid (22 mg, 0.36 mmole) and sodium triacetoxyborohydride (114 mg, 0.54mmole) were then added. After 2.75 h the reaction mixture was evaporatedto dryness. The residue was partitioned between ethyl acetate (50 ml)and saturated aqueous sodium bicarbonate (50 ml). The aqueous phase wasfurther extracted with ethyl acetate (25 ml). Combined extracts werewashed with brine (2×50 ml), dried (MgSO₄) and evaporated to a yellowgum. This was dissolved in hot ethanol (95% ca 3 ml) and the solutionwas treated with concentrated hydrochloric acid (0.71 mmole) to givewhite crystals of the title compound (107 mg). Found C, 48.41; H, 4.91;N, 15.68; F,14.52; C₂₁ H₂₂ F₄ N₆ O.2HCl (523.4) requires C, 48.19; H,4.62; N, 16.02%; F,14.26% Mass spectrum (thermospray +ve) m/e 451 (MH⁺).

Similarly prepared:

EXAMPLE 5[2-(2-Cyclopentoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidin-3-yl)amine dihydrochloride

From [2-(cyclopentoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)]-benzaldehyde(100 mg, 0.32 mmole) and ([2S,3S]-2-phenylpiperidin-3-yl)amine (54 mg,0.32 mmole) to give the title compound as a cream solid (114 mg), massspectrum (thermospray +ve) m/e 487 (MH⁺). R_(F) 0.41 (100:8:1dichloromethane: ethanol: ammonia).

EXAMPLE 6 a)3-{tert-Butoxycarbonyl-[2-(2-methoxy-1-ethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl-benzyl]-amino}[2S,3S]-2-phenylpiperidine-1-carboxylicacid tert-butyl ester

A solution of3-{tert-butoxycarbonyl-[2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-amino}-[2S,3S]-2-phenylpiperidine-1-carboxylicacid tert-butyl ester (177 mg) in dimethylformamide (0.5 ml) containinga suspension of finely ground potassium carbonate (39 mg) was stirredand treated with 2-chloroethylmethyl ether (280 mg) and potassium iodide(few crystals). The mixture was stirred at 44° for 9 days then at 60°for 2 days. The mixture was partitioned between ethyl acetate (25 ml)and 2M hydrochloric acid (25 ml). The aqueous phase was extracted withethyl acetate (25 ml) and the combined organic phases were washed withwater (25 ml) and brine (2×25 ml), dried (MgSO₄) and evaporated to givea brown gum. This was chromatographed on silica (Merck 9385) elutingwith 3:1 cyclohexane:ethyl acetate to give the title compound as a whitefoam (57 mg), mass spectrum (thermospray +ve) m/e 677 MH⁺). The titlecompound was deprotected according to conventional procedures to give:

b)[2-(2-methoxy-1-ethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenylpiperidine-3-yl)amine

A solution of3-{tert-Butoxycarbonyl-[2-(2-methoxy-1-ethoxy)-5-trifluoromethyl-tetrazol-1-yl)-benzyl]-amino}-[2S,3S]-2-phenylpiperidine-1carboxylicacid tert-butyl ester (54 mg, 0.08 mmol) in 4M hydrogen chloride indioxan (5 ml) was kept at 44° for 20 h and then evaporated to a whitefoam (48 mg). Trituration of this material with ether followed by dryingat 40° under vacuum gave the title compound (36 mg)

δ(D₂ O) 2.02 (2H, m), 2.18-2.38 and 2.38-2.58 (2H, 2m), 3.23-3.40 (1H,m), 3.43 (3H, s), 3.65-3.85 (3H, m), 3.91-4.25 (4H, m), 4.43 (1H, d,J=12 Hz), 4.9 (1H, d, J=3Hz), 7.14 (1H, d, J=8Hz), 7.25 (2H, d, J=7Hz),7.39-7.58 (4H, m), 7.69 (1H, dd, J=8, 2 Hz).

Assay: Found: C, 49.15%; H, 5.25%; N, 14.40%. C₂₃ H₂₇ F₃ N₆ O.C.7H₂ Orequires C, 49.15%; H. 5.45%; N, 14.95%.

PHARMACY EXAMPLES EXAMPLE A STERILE FORMULATION

    ______________________________________                                                               mg/ml                                                  ______________________________________                                        Compound of the invention                                                                            0.3     mg                                             Sodium Chloride USP    6.0     mg                                             Sodium Acetate USP     2.6     mg                                             Acetic Acid            1.1     mg                                             Water for Injection USP                                                                              qs to 1 ml                                             ______________________________________                                    

The components are dissolved in a portion of the water for injection andthe solution made up to final volume to provide 0.25 mg/ml of thecompound of the invention.

The solution may be packaged for injection, for example by filling andsealing in ampoules, vials or syringes. The ampoules, vials or syringesmay be aseptically filled and/or terminally sterilised by, for example,autoclaving at 121° C.

Tablets for Oral Administration

Tablets may be prepared by the normal methods such as direct compressionor wet granulation.

The tablets may be film coated with suitable film forming materials,such as Opadry White, type YS-1-7027, using standard techniques.Alternatively the tablets may be sugar coated.

EXAMPLE B

    ______________________________________                                        Direct Compression Tablet                                                                           mg/Tablet                                               ______________________________________                                        Compound of the invention                                                                           0.6      mg                                             Magnesium Stearate    0.75     mg                                             Avicel PH102          qs 150.00                                                                              mg                                             ______________________________________                                    

The compound of the invention is passed through a 30 mesh sieve andblended with Avicel PH102 and magnesium stearate. The resultant mix iscompressed into tablets using a suitable tablet machine fitted with9/32" diameter punches.

EXAMPLE C Wet Granulation

A formulation as described in Example B may be used. The compound of theinvention (dihydrochloride) is dissolved in a suitable volume ofgranulating solution (purified water or 10% PVP K29/32 in water). Afterdrying, the granules are screened, for example through 20 mesh screen,and blended with magnesium stearate. The granules are then compressedinto tablets as described in Example B.

EXAMPLE D Suppository

    ______________________________________                                        Compound of the invention                                                                           10.0     mg                                             Witepsol W32, hard fat                                                                              qs 2000.0                                                                              mg                                             ______________________________________                                    

Blend micronized drug in a portion of the melted Witepsol W32 atapproximately 36° C. for approximately 15 minutes in a high speed mixer.Incorporate the homogenized slurry into the remaining portion of themelted Witepsol W32 and blend at approximately 36° C. until satisfactorydispersion is achieved. Fill moulds with 2000 mg formulation.

EXAMPLE E Capsule

    ______________________________________                                                               mg/capsule                                             ______________________________________                                        Compound of the invention                                                                            12.0    mg                                             Polyethylene glycol    92.89   mg                                             Propylene glycol       qs 200  mg                                             ______________________________________                                    

Blend together polyethylene glycol and propylene glycol using heat asnecessary. Stir until homogeneous. Add micronised compound of theinvention to blend. Mix until homogenous. Fill into an appropriategelatin mass to give soft gelatin capsules containing 200 mg of theformulation.

EXAMPLE F Oral Syrup

    ______________________________________                                                               mg/ml                                                  ______________________________________                                        Compound of the invention                                                                            6.0    mg                                              Sucrose                200    mg                                              Methylparaben          1.2    mg                                              Propylparaben          0.15   mg                                              Flavouring             1.5    mg                                              Citric Acid            0.1    mg                                              Purified Water         qs 1   ml                                              ______________________________________                                    

Dissolve the parabens in a small portion of the water that has beenheated to approximately 90° C. Add the paraben solution to a largeportion of the remaining water with mixing. Add and dissolve the othercomponents. Bring the formulation to final volume and mix untilhomogenous. Fill the formulation into a container, such as a unit dosecup or a bottle for multiple-dose use.

We claim:
 1. A compound of formula (I) ##STR35## wherein R¹ is--O--(CH₂)_(p) C₃₋₇ cycloalkyl, --O--C₁₋₇ fluoroalkyl, or --O--(CH₂)_(n)X;R² is ##STR36## R³ is a hydrogen or halogen atom; R⁴ and R⁵ may eachindependently represent a hydrogen or halogen atom, or a C₁₋₄ alkyl,C₁₋₄ alkoxy or trifluoromethyl group; X is a C(O)--NR⁷ R⁸, C(O)R⁹, NR⁷R⁸, SO₂ NR⁷ R⁸, NHSO₂ R⁹, S(O)_(s) R⁹, OC₁₋₄ alkyl, NO₂, CO₂ H, CO₂ C₁₋₄alkyl, CN or, when n is 2, X may also represent OH, SH or NH₂ ; R⁶ is ahydrogen atom, a C₁₋₄ alkyl, (CH₂)_(m) cyclopropyl, --S(O)_(s) C₁₋₄alkyl, phenyl, NR¹⁰ R¹¹ , CH₂ C(O)CF₃, trifluoromethyl, difluoromethylor a cyano group; R⁷ and R⁸ may each independently represent hydrogenatoms or a C₁₋₄ alkyl group; R⁹ represents a C₁₋₄ alkyl ortrifluoromethyl group; R¹⁰ and R¹¹ may each independently represent ahydrogen atom, or a C₁₋₄ alkyl or acyl group; x represents zero or 1; nis 1 or 2; s represents zero, 1 or 2; m represents zero or 1; prepresents zero or 1; or a pharmaceutically acceptable salt or solvatethereof, with the proviso that when R¹ is --O--(CH₂)_(n) CHF₂ or--O--(CH₂)_(n) CN, R² is ##STR37## and x is zero.
 2. A compoundaccording to claim 1 whereinR² is ##STR38## x is zero and R³, R⁴ and R⁵are each hydrogen atoms.
 3. A compound according to claim 1 wherein R¹is a cyclopropylmethoxy, cyclopentyloxy, difluoromethyloxy,trifluoromethyloxy, 2,2,2-trifluoroethyloxy, fluoromethyloxy, OCH₂ OMeor O--CH₂ CH₂ OMe group.
 4. A compound according to claim 1 wherein R⁶is a hydrogen atom or a C₁₋₄ alkyl or a trifluoromethyl group.
 5. Acompound whichis(2-Cyclopentoxy-5-tetrazol-1-ylbenzyl)-(-2-phenylpiperidin-3-yl)amine; (2-Cyclopropylmethoxy-5-tetrazol-1-ylbenzyl)-(-2-phenylpiperidin-3-yl)amine;(2-Cyclopentoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(-2-phenylpiperidin-3-yl)amine,(2-Cyclopropylmethoxy-5-(5-trifluoromethyltetrazol-1-yl )benzyl)-(-2-phenylpiperidin-3-yl)amine;(2-Fluoromethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(-2-phenylpiperidin-3-yl)amine;[2-(2-methoxy-1-ethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(-2-phenylpiperidine-3-yl)amineor a pharmaceutically acceptable salt or solvate thereof.
 6. Apharmaceutical composition comprising a compound according to claim 1 ora pharmaceutically acceptable salt or solvate thereof, together with apharmaceutically acceptable carrier.
 7. A method for the treatment of acondition mediated by tachykinins, including substance P and otherneurokinins, in a mammal wherein the conditions are susceptible totreatment by antagonism of the binding of tachykinin to NK1 receptorcomprising administration of an effective amount of a compound accordingto claim 1, or a pharmaceutically acceptable derivative thereof.
 8. Aprocess for preparing a compound of formula (I) as defined in claim 1,or a pharmaceutically acceptable salt or solvate thereof whichcomprises:(A) reacting a compound of formula (II) ##STR39## with acompound of formula (III) ##STR40## followed by reduction: or (B) aprocess for preparing a compound of formula (I) where R² is a group (A)as defined hereinbefore, x is zero and R⁶ is --NH₂ which comprisesreacting a compound of formula (XXIV) ##STR41## with ammonium chlorideand sodium azide: or (C) reducing a compound of formula (XXV) ##STR42##(D) a process for preparing compounds of formula (I), excludingcompounds where R¹ represents cyclopropyloxy, cyclobutyloxy andtrifluoromethyloxy which comprises reacting a compound of formula(XXVII) ##STR43## or an amino-protected derivative thereof, withL-(CH₂)_(p) C₃₋₇ cycloalkyl or L-C₁₋₇ fluoroalkyl where p is as definedhereinbefore and L represents a suitable leaving group in the presenceof a base followed by deprotection where necessary: or (E) a process forpreparing compounds of formula (I) where R² is a group A as definedabove and R⁶ represents cyano which comprises reacting a compound offormula (XXIX) ##STR44## where L represents a suitable leaving group,with potassium cyanide.